EDITORIAL COMMENT
Effects of shear stress and flow pulsatility on endothelial function
Insights gleaned from external counterpulsation therapy*
Joseph A. Vita, MD, FACC ,* and
Gary F. Mitchell, MD
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
Cardiovascular Engineering, Inc., Holliston, Massachusetts, USA
* Reprint requests and correspondence: Dr. Joseph A. Vita, Section of Cardiology, Boston Medical Center, 88 East Newton Street, Boston, Massachusetts 02118, USA.
jvita{at}bu.edu
Poised at the interface between flowing blood and the vascular wall, the endothelium transduces biological and physical stimuli within the circulation into physiological responses that affect vascular and tissue homeostasis. There currently is great interest in the importance of abnormalities of endothelial cell function for the development of atherosclerosis. When exposed to conditions that mimic cardiovascular disease risk factors, cultured endothelial cells adopt a proinflammatory, pro-thrombotic, vasoconstrictor, and growth-promoting phenotype that is relevant to atherogenesis and cardiovascular disease events (1). Studies in patients have shown that endothelial dysfunction, as reflected by impaired endothelium-dependent vasodilation, is associated with increased risk for cardiovascular disease events (for a review, see Widlansky et al. [2]). Serum markers of endothelial activation may provide similar prognostic information (2,3). Furthermore, many interventions that improve endothelial function have been shown to reduce cardiovascular risk, including lipid-lowering therapy, angiotensin-converting enzyme inhibitors, smoking cessation, and physical exercise (2). These observations have promoted speculation that endothelial function may serve as a "barometer" for the cumulative effects of risk factors and therapies on vascular health (4).
For many years, investigators have recognized that local rheologic forces influence endothelial phenotype and impact atherogenesis. Although the entire arterial tree is exposed to systemic risk factors, atherosclerosis has a predilection for branch points and other regions of disordered flow (5). The effects of local shear stress on endothelial phenotype may account for this observation (6). In general, laminar shear stress maintains normal endothelial structure and function, whereas stasis, turbulent flow, and local shear gradients activate endothelial cells and induce a pro-atherogenic state that includes reduced expression of endothelial nitric oxide synthase (eNOS) and increased expression of vasoconstrictor and pro-inflammatory factors (7). The pulsatile pattern of shear stress also affects the endothelium. Thus, rapidly changing flow and oscillatory flow with flow reversal and low net flow tends to induce a more pathologic state compared with laminar flow or oscillatory flow that remains unidirectional (7–9). These adverse effects are associated with increased oxidative stress in the vascular wall (10,11). However, the compliance of the underlying arterial wall importantly modulates the consequences of oscillatory flow. If the artery has normal distensibility, oscillatory flow may actually be cytoprotective, but the same stimulus has an adverse effect in a non-compliant vessel (12,13). There also is evidence that increasing the frequency of pulsations may be advantageous (14). Finally, higher pulse pressure, which relates strongly to stiffness of central arterial vessels (15), is associated with endothelial dysfunction (16). Thus, it is apparent that arterial flow patterns, vascular compliance, and pulse pressure may have complex and interacting effects on endothelial cells and other components of the vascular wall.
In whole animals and in human subjects, local shear stress has short- and long-term effects. Acute increases in arterial flow stimulate release of nitric oxide and other endothelium-derived relaxing factors that dilate the artery and restore shear stress toward normal (17). In humans, this response has been demonstrated in normal coronary arteries and is impaired in the presence of atherosclerosis (18). Flow-mediated dilation may be examined non-invasively in the brachial artery using reactive hyperemia to induce a transient increase in shear stress (19). Brachial artery flow-mediated dilation has been shown to depend on nitric oxide synthesis (20), and an abnormal response may predict cardiovascular disease events (21). Longer-term increases in flow produce changes in endothelial shape, alignment, and the expression of genes associated with a healthy phenotype, including increased expression of eNOS (5). Furthermore, increased flow has profound effects on arterial structure, including increased arterial size through remodeling and effects on growth of new vessels through angiogenesis (5). Repetitive short-term increases in flow appear to have similar beneficial effects and are believed to contribute to the antiatherosclerotic effects of physical exercise in coronary (22,23) and peripheral arteries (24).
In this issue of the Journal, Shechter et al. (25) report the results of a study that examined another intervention that influences arterial flow and pulsatility and its effects on endothelial function. External counterpulsation therapy (ECP) is considered an "alternative" therapy for patients with intractable coronary artery disease (for a recent comprehensive review, see Bonetti et al. [26]). During ECP, patients lie supine while cuffs on the lower extremities are repeatedly inflated in a sequential distal-to-proximal manner during diastole. Thus, ECP induces retrograde flow of blood from the lower extremities into the central aorta and produces a large diastolic pressure wave that increases coronary perfusion pressure and flow in a manner reminiscent of intra-aortic balloon pumping. This counterpulsation-induced "reflected wave" represents an exaggeration of the normal pattern of diastolic wave reflection found in young, healthy adults (27). Rapid deflation of the cuffs immediately before systole decreases myocardial afterload and myocardial oxygen demand. In the arm, flow increases markedly during diastole, and ECP thereby transiently eliminates exposure to repetitive and potentially deleterious diastolic stasis or flow reversal (26). In the reported study, 20 patients with severe coronary artery disease and intractable angina pectoris received ECP for 1 h per day, 5 days per week for 7 weeks. As has been previously reported, the subjects had subjective improvement of angina symptoms and reported less nitroglycerin use (26). In addition, brachial artery flow-mediated dilation improved markedly, whereas the dilator response to sublingual nitroglycerin remained unchanged. A control group of 20 comparable patients who had declined ECP therapy had no change in symptoms and no change in vasodilator function over the same period of time.
As Shechter et al. (25) point out, the major weakness of the study is the lack of a randomized control group. It is unclear why the non-randomized control patients declined therapy and whether there was some other difference between groups. The study also would have been more convincing if the control group had received sham therapy. Shechter et al. (25) do not report the effect of ECP on baseline brachial artery diameter, and because flow-mediated dilation relates strongly to this variable, it is possible the results reflect an effect of treatment on resting arterial tone or vessel size, rather than conduit artery endothelial vasodilator function. Furthermore, the investigators did not examine the effect of therapy on the extent of reactive hyperemia, which determines the evoked shear stress in the brachial artery and, thus, serves as the stimulus to flow-mediated dilation. It remains distinctly possible that ECP had an effect on resistance vessels, rather than the conduit brachial artery. A preliminary study does suggest that ECP improves function of small vessels in the finger during reactive hyperemia (28). Indeed, the potential effects of increased flow on coronary microvascular function, remodeling, and angiogenesis, leading to improved collateral flow are believed to be important mechanisms of benefit for ECP (26).
Despite these limitations, the study represents an interesting examination of the physiologic consequences of altered pulsatility and flow on conduit arteries, and several potential mechanisms might be considered. As occurs during upper extremity exercise, ECP increases upper extremity blood flow, and this effect has the potential to increase eNOS expression and improve endothelial function in the conduit brachial artery. The ECP therapy doubles the number of arterial pulsations per cardiac cycle, which could be beneficial given the relationship between pulsation frequency and endothelial function (14). Aging, hypertension, and other forms of cardiovascular disease are associated with increased stiffness of the central aorta, and as a result, flow in the brachial artery becomes more oscillatory and flow reversal may occur during diastole (15). The ECP therapy has the potential to markedly augment forward flow during diastole and limit flow reversal, and this altered flow pattern could in itself have a beneficial effect.
In summary, the study by Shechter et al. (25) provides additional evidence that ECP relieves angina symptoms in patients with severe coronary artery disease and supports the hypothesis that improved endothelial function is a mechanism of benefit. Further studies would be required to confirm that this effect has occurred in the coronary circulation and to determine whether improvement of endothelial function in this fashion has any effect on cardiovascular events in these high-risk patients. An interesting additional implication of the study relates to rheologic consequences of ECP. It is now clear that the various forms of local shear stress and the pulsatile patterns of flow and blood pressure have important effects on the vasculature and the heart that are relevant to cardiovascular disease. The vascular endothelium plays a major role in transducing these physical forces into adaptive physiologic responses, and loss of these homeostatic mechanisms is an important consequence of endothelial dysfunction that merits investigation and serves as a target for therapy.
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Footnotes
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Dr. Vita's work is supported in part by a Specialized Center of Research in Ischemic Heart Disease grant from the National Institutes of Health (NIH) (HL55993), the General Clinical Research Center, Boston Medical Center (M01RR00533), and by NIH grants PO1HL60886 and HL52936. Dr. Mitchell's work is supported in part by NIH grant R01HL70100. Jonathon Abrams, MD, FACC, acted as Guest Editor for this editorial comment.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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